title: Suppression of acute graft-versus-host response by TCDD is independent of the CTLA-4-IFN-γ-IDO pathway.
abstract: Activation of the aryl hydrocarbon receptor (AhR) by its prototypic ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces potent suppression of an acute graft-versus-host (GVH) response and prevents GVH disease (GVHD). Suppression is associated with development of a regulatory population of donor CD4(+) CD25(+)T-cells that express high levels of cytotoxic T-lymphocyte antigen 4 (CTLA-4). However, a direct link between these AhR-induced Tregs (AhR-Tregs) and suppression of GVHD remains to be shown. CTLA-4 is a negative regulator of T-cell responses and is associated with the induction of tolerogenic dendritic cells (DCs) that produce indoleamine 2,3-dioxygenase (IDO). We hypothesized that AhR-Tregs mediate suppression via their enhanced expression of CTLA-4, which, in turn, induces IFN-γ and IDO in host DCs. Subsequent depletion of tryptophan by IDO leads to termination of the donor T-cell response prior to development of effector CTL. Here, we show that despite increased expression of Ifng, Irf3, Irf7, Ido1, and Ido2 in the lymph nodes of TCDD-treated host mice, inhibition of IDO enzyme activity by 1-methyl-tryptophan was unable to relieve TCDD-mediated suppression of the GVH response. Furthermore, treatment with an anti-CTLA-4 antibody that blocks CTLA-4 signaling was also unable to alleviate TCDD-mediated suppression. Alternatively, we investigated the possibility that donor-derived AhR-Tregs produce IFN-γ to suppress effector CTL development. However, suppression of GVHD by TCDD was not affected by the use of Ifng-deficient donor cells. Together, these results indicate that neither overexpression of CTLA-4 nor production of IFN-γ by AhR-Tregs plays a major role in the manifestation of their immunosuppressive function in vivo.
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Rohlman
authors.forename: Sumit
authors.initials: S
authors.lastname: Punj
authors.forename: Jamie
authors.initials: J
authors.lastname: Pennington
authors.forename: Sam
authors.initials: S
authors.lastname: Bradford
authors.forename: Nancy I
authors.initials: NI
authors.lastname: Kerkvliet
mesh_terms: D000208:Acute Disease; D000818:Animals; D060908:CTLA-4 Antigen / Q000502:physiology*; D006086:Graft vs Host Disease / Q000517:prevention & control*; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D060908:CTLA-4 Antigen; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D007371:Interferon-gamma
keywords: CTLA-4; GVHD; IDO; T-regulatory cell.; TCDD